Epidemiology

The prevalence of congenital hypothyroidism based on nationwide programs for neonatal screening is 1/3,000 infants worldwide; studies from the United States report that the prevalence is lower in black Americans and higher in Asian-Americans and Pacific islanders, Hispanics, and Native Americans. Twice as many girls as boys are affected.

Etiology

Thyroid Hormone Unresponsiveness

This autosomal dominant disorder is caused by mutations in the thyroid hormone receptor. Most patients have a goiter, and levels of T₄, T₃, free T₄, and free T₃ are elevated. These findings often have led to the erroneous diagnosis of Graves disease, although most affected patients are clinically euthyroid. The unresponsiveness can vary among tissues. There may be subtle clinical features of hypothyroidism, including mild mental retardation, growth retardation, and delayed skeletal maturation. On the other hand, there may be clinical features compatible with hyperthyroidism, such as tachycardia and hyperreflexia. It is presumed that these patients have varying tissue resistance to thyroid hormone. One neurologic manifestation is an increased association of attention-deficit/hyperactivity disorder; the converse is not true because patients with attention-deficit/hyperactivity disorder do not have an increased risk of thyroid hormone resistance.

TSH levels are diagnostic in that they are not suppressed as in Graves disease but instead are moderately elevated or normal but inappropriate for the levels of T₄ and T₃. The failure of TSH suppression indicates that the resistance is generalized and affects the pituitary gland as well as peripheral tissues. More than 40 distinct point mutations in the hormone-binding domain of the β-thyroid receptor have been identified. Different phenotypes do not correlate with genotypes. The same mutation has been observed in patients with generalized or isolated pituitary resistance, even in different members of the same family. A child homozygous for the receptor mutation showed unusually severe resistance. These cases support the dominant negative effect of mutant receptors, in which the mutant receptor protein inhibits normal receptor action in heterozygotes. Elevated levels of T₄ on neonatal thyroid screening should suggest the possibility of this diagnosis. No treatment is usually required unless growth and skeletal retardation are present.

Two infants of consanguineous matings are known to have an autosomal recessive form of thyroid resistance. These infants had manifestations of hypothyroidism early in life, and genetic studies revealed a major deletion of the β-thyroid receptor in 1 of them. The resistance appears to be more severe in this form of the entity.

On rare occasions, resistance to thyroid hormone selectively affects the pituitary gland. Because the peripheral tissues are not resistant to thyroid hormones, the patient has a goiter and manifestations of hyperthyroidism. The laboratory findings are the same as those seen with generalized thyroid hormone resistance. This condition must be differentiated from a pituitary TSH-secreting tumor. Different treatments, including D-thyroxine, TRIAC (triiodothyroacetic acid), and TETRAC (tetraiodothyroacetic acid) have been successful in some patients. Bromocriptine administration, which interferes with TSH secretion, was reported to be successful in another patient. Whether isolated pituitary resistance to thyroid hormone exists as a distinct entity is controversial; it may be a variant of generalized resistance to thyroid hormone with varying tissue responsiveness.

Thyroid Function in Preterm Babies

Postnatal thyroid function in preterm babies is qualitatively similar but quantitatively reduced compared with that of term infants. The cord serum T₄ is decreased in proportion to gestational age and birthweight. The postnatal TSH surge is reduced, and infants with complications of prematurity, such as respiratory distress syndrome, actually experience a decrease in serum T₄ in the 1st wk of life. As these complications resolve, the serum T₄ gradually increases so that generally by 6 wk of life it enters the T₄ range seen in term infants. Serum free T₄ concentrations seem less affected, and when measured by equilibrium dialysis, these levels are often normal. Preterm babies also have a higher incidence of transient TSH elevations and apparent transient primary hypothyroidism. Premature infants <28 wk of gestation might have problems resulting from a combination of immaturity of the hypothalamic-pituitary-thyroid axis and loss of the maternal contribution of thyroid hormone and so may be candidates for temporary thyroid hormone replacement; further studies are needed.

Clinical Manifestations

Most infants with congenital hypothyroidism are asymptomatic at birth, even if there is complete agenesis of the thyroid gland. This situation is attributed to the transplacental passage of moderate amounts of maternal T₄, which provides fetal levels that are approximately 33% of normal at birth. Despite this maternal contribution of thyroxine, hypothyroid infants still have a low serum T₄ and elevated TSH level and so will be identified by newborn screening programs.

The clinician depends on neonatal screening tests for the diagnosis of congenital hypothyroidism. Laboratory errors occur, and awareness of early symptoms and signs must be maintained. Congenital hypothyroidism is twice as common in girls as in boys. Before neonatal screening programs, congenital hypothyroidism was rarely recognized in the newborn because the signs and symptoms are usually not sufficiently developed. It can be suspected and the diagnosis established during the early weeks of life if the initial but less characteristic manifestations are recognized. Birthweight and length are normal, but head size may be slightly increased because of myxedema of the brain. Prolongation of physiologic jaundice, caused by delayed maturation of glucuronide conjugation, may be the earliest sign. Feeding difficulties, especially sluggishness, lack of interest, somnolence, and choking spells during nursing, are often present during the 1st mo of life. Respiratory difficulties, due in part to the large tongue, include apneic episodes, noisy respirations, and nasal obstruction. Typically, respiratory distress syndrome also occurs. Affected infants cry little, sleep much, have poor appetites, and are generally sluggish. There may be constipation that does not usually respond to treatment. The abdomen is large, and an umbilical hernia is usually present. The temperature is subnormal, often <35°C (95°F), and the skin, particularly that of the extremities, may be cold and mottled. Edema of the genitals and extremities may be present. The pulse is slow, and heart murmurs, cardiomegaly, and asymptomatic pericardial effusion are common. Macrocytic anemia is often present and is refractory to treatment with hematinics. Because symptoms appear gradually, the clinical diagnosis is often delayed.

Approximately 10% of infants with congenital hypothyroidism have associated congenital anomalies. Cardiac anomalies are most common, but anomalies of the nervous system and eye have also been reported. Infants with congenital hypothyroidism may have associated hearing loss.

If congenital hypothyroidism goes undetected and untreated, these manifestations progress. Retardation of physical and mental development becomes greater during the following months, and by 3-6 mo of age the clinical picture is fully developed (Fig. 559-1). When there is only partial deficiency of thyroid hormone, the symptoms may be milder, the syndrome incomplete, and the onset delayed. Although breast milk contains significant amounts of thyroid hormones, particularly T₃, it is inadequate to protect the breast-fed infant who has congenital hypothyroidism, and it has no effect on neonatal thyroid screening tests.

Figure 559-1 Congenital hypothyroidism in an infant 6 mo of age. The infant ate poorly in the neonatal period and was constipated. She had a persistent nasal discharge and a large tongue; she was very lethargic and had no social smile and no head control. A, Notice the puffy face, dull expression, and hirsute forehead. Tests revealed a negligible uptake of radioiodine. Osseous development was that of a newborn. B, Four months after treatment, note the decreased puffiness of the face, the decreased hirsutism of the forehead, and the alert appearance.

The child’s growth will be stunted, the extremities are short, and the head size is normal or even increased. The anterior and posterior fontanels are open widely; observation of this sign at birth can serve as an initial clue to the early recognition of congenital hypothyroidism. Only 3% of normal newborn infants have a posterior fontanel larger than 0.5 cm. The eyes appear far apart, and the bridge of the broad nose is depressed. The palpebral fissures are narrow and the eyelids are swollen. The mouth is kept open, and the thick, broad tongue protrudes. Dentition will be delayed. The neck is short and thick, and there may be deposits of fat above the clavicles and between the neck and shoulders. The hands are broad and the fingers are short. The skin is dry and scaly, and there is little perspiration. Myxedema is manifested, particularly in the skin of the eyelids, the back of the hands, and the external genitals. The skin shows general pallor with a sallow complexion. Carotenemia can cause a yellow discoloration of the skin, but the sclerae remain white. The scalp is thickened, and the hair is coarse, brittle, and scanty. The hairline reaches far down on the forehead, which usually appears wrinkled, especially when the infant cries.

Development is usually delayed. Hypothyroid infants appear lethargic and are late in learning to sit and stand. The voice is hoarse, and they do not learn to talk. The degree of physical and mental retardation increases with age. Sexual maturation may be delayed or might not take place at all.

The muscles are usually hypotonic, but in rare instances generalized muscular pseudohypertrophy occurs (Kocher-Debré-Sémélaigne syndrome). Affected older children can have an athletic appearance because of pseudohypertrophy, particularly in the calf muscles. Its pathogenesis is unknown; nonspecific histochemical and ultrastructural changes seen on muscle biopsy return to normal with treatment. Boys are more prone to development of the syndrome, which has been observed in siblings born from a consanguineous mating. Affected patients have hypothyroidism of longer duration and severity.

Some infants with mild congenital hypothyroidism have normal thyroid function at birth and so are not identified by newborn screening programs. In particular, some children with ectopic thyroid tissue (lingual, sublingual, subhyoid) produce adequate amounts of thyroid hormone for many years, or it eventually fails in early childhood. Affected children come to clinical attention because of a growing mass at the base of the tongue or in the midline of the neck, usually at the level of the hyoid. Occasionally, ectopia is associated with thyroglossal duct cysts. It can occur in siblings. Surgical removal of ectopic thyroid tissue from a euthyroid patient usually results in hypothyroidism, because most such patients have no other thyroid tissue.

Laboratory Findings

In developed countries, infants with congenital hypothyroidism are identified by newborn screening programs. Blood obtained by heel-prick between 2 and 5 days of life is placed on a filter paper card and sent to a central screening laboratory. Many newborn screening programs in North America and Europe measure levels of T₄, followed by measurement of TSH when T₄ is low. This approach identifies infants with primary hypothyroidism, some with hypothalamic or pituitary hypothyroidism, and infants with a delayed increase in TSH levels. Other neonatal screening programs in North America, Europe, Japan, Australia, and New Zealand are based on a primary measurement of TSH. This approach detects infants with primary hypothyroidism and can detect infants with subclinical hypothyroidism (normal T₄, elevated TSH), but it misses infants with delayed TSH elevation and with hypothalamic or pituitary hypothyroidism. With any of these tests, special care should be given to the normal range of values for age of the patient, particularly in the 1st weeks of life (Table 559-2). Regardless of the approach used for screening, some infants escape detection because of technical or human errors; clinicians must maintain their vigilance for clinical manifestations of hypothyroidism.

Serum levels of T₄ or free T₄ are low; serum levels of T₃ may be normal and are not helpful in the diagnosis. If the defect is primarily in the thyroid, levels of TSH are elevated, often to >100 mU/L. Serum levels of thyroglobulin are usually low in infants with thyroid agenesis or defects of thyroglobulin synthesis or secretion, whereas they are elevated with ectopic glands and other inborn errors of thyroxine synthesis, but there is a wide overlap of ranges.

Special attention should be paid to identical twins; in several reported cases, neonatal screening failed to detect the discordant twin with hypothyroidism, and the diagnosis was not made until the infants were 4-5 mo of age. Apparently, transfusion of euthyroid blood from the unaffected twin normalized the serum level of T₄ and TSH in the affected twin at the initial screening. Many newborn screening programs perform a routine second test in same-sex twins.

Retardation of osseous development can be shown radiographically at birth in about 60% of congenitally hypothyroid infants and indicates some deprivation of thyroid hormone during intrauterine life. The distal femoral epiphysis, normally present at birth, is often absent (Fig. 559-2A). In undetected and untreated patients, the discrepancy between chronologic age and osseous development increases. The epiphyses often have multiple foci of ossification (epiphyseal dysgenesis) (Fig. 559-2B); deformity (“beaking”) of the 12th thoracic or 1st or 2nd lumbar vertebra is common. Roentgenograms of the skull show large fontanels and wide sutures; intersutural (wormian) bones are common. The sella turcica is often enlarged and round; in rare instances, there may be erosion and thinning. Formation and eruption of teeth can be delayed. Cardiac enlargement or pericardial effusion may be present.

Figure 559-2 Congenital hypothyroidism. A, Absence of distal femoral epiphysis in a 3 mo old infant who was born at term. This is evidence for the onset of the hypothyroid state during fetal life. B, Epiphyseal dysgenesis in the head of the humerus in a 9 yr old girl who had been inadequately treated with thyroid hormone.

Scintigraphy can help to pinpoint the underlying cause in infants with congenital hypothyroidism, but treatment should not be unduly delayed for this study. ¹²³I-sodium iodide is superior to ^99mTc-sodium pertechnetate for this purpose. Ultrasonographic examination of the thyroid is helpful, but studies show it can miss some ectopic glands shown by scintigraphy. Demonstration of ectopic thyroid tissue is diagnostic of thyroid dysgenesis and establishes the need for lifelong treatment with T₄. Failure to demonstrate any thyroid tissue suggests thyroid aplasia, but this also occurs in neonates with TRBAb and in infants with the iodide-trapping defect. A normally situated thyroid gland with a normal or avid uptake of radionuclide indicates a defect in thyroid hormone biosynthesis. In the past, patients with goitrous hypothyroidism have required extensive evaluation, including radioiodine studies, perchlorate discharge tests, kinetic studies, chromatography, and studies of thyroid tissue, to determine the biochemical nature of the defect. Most can be evaluated by genetic studies looking for defects in the steps along the thyroxine biosynthetic pathway.

The electrocardiogram may show low-voltage P and T waves with diminished amplitude of QRS complexes and suggest poor left ventricular function and pericardial effusion. Echocardiography can confirm a pericardial effusion. The electroencephalogram often shows low voltage. In children >2 yr of age, the serum cholesterol level is usually elevated. Brain MRI before treatment is reportedly normal, although proton magnetic resonance spectroscopy shows high levels of choline-containing compounds, which can reflect blocks in myelin maturation.

Treatment

Levothyroxine given orally is the treatment of choice. Because 80% of circulating T₃ is formed by monodeiodination of T₄, serum levels of T₄ and T₃ in treated infants return to normal. This is also true in the brain, where 80% of required T₃ is produced locally from circulating T₄. The optimal dose of levothyroxine is controversial. Higher dosages can normalize T₄ more quickly and lead to improvement in cognitive scores, but there is some suggestion that children treated with these high doses are more likely to develop behavioral difficulties later on. In one study of neonates treated with dosages that ranged between 25 and 50 µg/day, infants treated with 50 µg/day attained normal thyroid function sooner, but there was no difference in rate of growth of length, weight, or head circumference between 3 and 18 mo of age as a function of levothyroxine dose. Currently, in neonates, the recommended initial starting dose is 10-15 µg/kg/day (totaling 37.5-50 µg/day). The starting dose can be tailored to the severity of hypothyroidism. Newborns with more severe hypothyroidism, as judged by a serum T₄ <5 µg/dL, should be started at the higher end of the dosage range. Thyroxine tablets should not be mixed with soy protein formulas, concentrated iron, or calcium, because these can bind T₄ and inhibit its absorption.

Levels of serum T₄ or free T₄ and TSH should be monitored at recommended intervals (approximately monthly in the first 6 mo of life, and then every 2-3 mo between 6 mo and 2 yr) and maintained in the normal range for age. The dose of levothyroxine on a weight basis gradually decreases with age. Children with hypothyroidism require about 4 µg/kg/24 hr, and adults require only 2 µg/kg/24 hr.

Later, confirmation of the diagnosis may be necessary for some infants to rule out the possibility of transient hypothyroidism. This is unnecessary in infants with proven thyroid ectopia or in those who manifest elevated levels of TSH after 6-12 mo of therapy because of poor compliance or an inadequate dose of T₄. Discontinuation of therapy at about 3 yr of age for 3-4 wk results in a marked increase in TSH levels in children with permanent hypothyroidism.

The only untoward effects of sodium-L-thyroxine are related to its dosage. Overtreatment can risk craniosynostosis and temperament problems.

Prognosis

Thyroid hormone is critical for normal cerebral development in the early postnatal months; biochemical diagnosis must be made soon after birth, and effective treatment must be initiated promptly to prevent irreversible brain damage. With the advent of neonatal screening programs for detection of congenital hypothyroidism, the prognosis for affected infants has improved dramatically. Early diagnosis and adequate treatment from the first weeks of life result in normal linear growth and intelligence comparable with that of unaffected siblings. Some screening programs report that the most severely affected infants, as judged by the lowest T₄ levels and retarded skeletal maturation, have reduced (5-10 points) IQs and other neuropsychological sequelae, such as incoordination, hypotonia or hypertonia, short attention span, and speech problems even with early diagnosis and adequate treatment. Psychometric testing can show problems with vocabulary and reading comprehension, arithmetic, and memory. Approximately 20% of children have a neurosensory hearing deficit.

Delay in diagnosis, failure to correct initial hypothyroxinemia rapidly, inadequate treatment, and poor compliance in the first 2-3 yr of life result in variable degrees of brain damage. Without treatment, affected infants are profoundly mentally deficient and growth retarded. When onset of hypothyroidism occurs after 2 yr of age, the outlook for normal development is much better even if diagnosis and treatment have been delayed, indicating how much more important thyroid hormone is to the rapidly growing brain of the infant.

Epidemiology

Studies of school-aged children report that hypothyroidism occurs in approximately 0.3% (1/333). Subclinical hypothyroidism (TSH >4.5 mU/L, normal T₄ or free T₄) is more common, occurring in approximately 2% of adolescents. Acquired hypothyroidism is most commonly a result of chronic lymphocytic thyroiditis; 6% of children aged 12-19 yr have evidence of autoimmune thyroid disease, which occurs with a 2 : 1 female : male preponderance.

Etiology

The most common cause of acquired hypothyroidism (Table 559-3) is chronic lymphocytic thyroiditis (Chapter 560). Autoimmune thyroid disease may be part of polyglandular syndromes; children with Down, Turner, and Klinefelter syndromes and celiac disease or diabetes are at higher risk for associated autoimmune thyroid disease (Chapter 560). In children with Down syndrome, anti-thyroid antibodies develop in approximately 30%, and subclinical or overt hypothyroidism occurs in approximately 15-20%. In girls with Turner syndrome, anti-thyroid antibodies develop in approximately 40%, and subclinical or overt hypothyroidism occurs in approximately 15-30%, rising with increasing age. In children with type 1 diabetes mellitus, approximately 20% develop anti-thyroid antibodies and 5% become hypothyroid. Additional autoimmune diseases with an increased risk of hypothyroidism include Sjögren syndrome, multiple sclerosis, pernicious anemia, Addison disease, and ovarian failure. Although typically seen in adolescence, it occurs as early as in the 1st yr of life. Williams syndrome is associated with subclinical hypothyroidism; this does not appear to be autoimmune, as anti-thyroid antibodies are negative.

Thyroidectomy for thyrotoxicosis or cancer results in hypothyroidism, as can removal of ectopic thyroid tissue. Thyroid tissue in a thyroglossal duct cyst usually constitutes the only source of thyroid hormone, and excision results in hypothyroidism. Because subhyoid glands usually mimic thyroglossal duct cysts, ultrasonographic examination or a radionuclide scan before surgery is indicated in these patients.

Irradiation of the area of thyroid that is incidental to the treatment of Hodgkin disease or other head and neck malignancies or that is administered before bone marrow transplantation often results in thyroid damage. About 30% of such children acquire elevated TSH levels within a yr after therapy, and another 15-20% progress to hypothyroidism within 5-7 yr. Some clinicians recommend periodic TSH measurements, but others recommend treatment of all exposed patients with doses of T₄ to suppress TSH.

Protracted ingestion of medications containing iodides—for example, expectorants—can cause hypothyroidism, usually accompanied by goiter (Chapter 561). Amiodarone, a drug used for cardiac arrhythmias and consisting of 37% iodine by weight, causes hypothyroidism in about 20% of treated children. It affects thyroid function directly by its high iodine content as well as by inhibition of 5′-deiodinase, which converts T₄ to T₃. Children treated with this drug should have serial measurements of T₄, T₃, and TSH. Children with Graves’ disease treated with anti-thyroid drugs (methimazole or propylthiouracil) can develop hypothyroidism. Additional drugs that can produce hypothyroidism include lithium carbonate, interferon alpha, stavudine, thalidomide, valproate (subclinical), and aminoglutethimide.

Children with nephropathic cystinosis, a disorder characterized by intralysosomal storage of cystine in body tissues, acquire impaired thyroid function. Hypothyroidism may be overt, but subclinical forms are more common, and periodic assessment of TSH levels is indicated. By 13 yr of age, two thirds of these patients require T₄ replacement.

Histiocytic infiltration of the thyroid in children with Langerhans cell histiocytosis can result in hypothyroidism.

Children with chronic hepatitis C infection are at risk for subclinical hypothyroidism; this does not appear to be autoimmune, because anti-thyroid antibodies are negative.

Hypothyroidism can occur in children with large hemangiomas of the liver, because of increased type 3 deiodinase activity, which catalyzes conversion of T₄ to rT₃ and T₃ to T₂. Thyroid secretion is increased, but it is not sufficient to compensate for the large increase in degradation of T₄ to rT₃.

Some patients with congenital thyroid dysgenesis and residual thyroid function or with incomplete genetic defects in thyroid hormone synthesis do not display clinical manifestations until childhood and appear to have acquired hypothyroidism. Although these conditions are usually now detected by newborn screening programs, very mild defects can escape detection.

Any hypothalamic or pituitary disease can cause acquired central hypothyroidism (Chapter 551). TSH deficiency may be the result of a hypothalamic-pituitary tumor (craniopharyngioma most common in children) or a result of treatment for the tumor. Other causes include cranial radiation, head trauma, or diseases infiltrating the pituitary gland, such as Langerhans cell histiocytosis.

Clinical Manifestations

Deceleration of growth is usually the first clinical manifestation, but this sign often goes unrecognized (Figs. 559-3 and 559-4). Goiter, which may be a presenting feature, typically is nontender and firm, with a rubbery consistency and a pebbly surface. Weight gain is mostly fluid retention (myxedema), not true obesity. Myxedematous changes of the skin, constipation, cold intolerance, decreased energy, and an increased need for sleep develop insidiously. Surprisingly, schoolwork and grades usually do not suffer, even in severely hypothyroid children. Additional features include bradycardia, muscle weakness or cramps, nerve entrapment, and ataxia. Osseous maturation is delayed, often strikingly, which is an indication of the duration of the hypothyroidism. Adolescents typically have delayed puberty; older adolescent girls manifest menometrorhhagia. Younger children might present with galactorrhea or pseudoprecocious puberty. Galactorrhea is a result of increased TRH stimulating prolactin secretion. The precocious puberty, characterized by breast development in girls and macro-orchidism in boys, is thought to be the result of abnormally high TSH concentrations binding to the FSH, receptor with subsequent stimulation.

Figure 559-3 A, Acquired hypothyroidism in a girl 6 yr of age. She was treated with a wide variety of hematinics for refractory anemia for 3 yr. She had almost complete cessation of growth, constipation, and sluggishness for 3 yr. The height age was 3 yr; the bone age was 4 yr. She had a sallow complexion and immature facies with a poorly developed nasal bridge. Serum cholesterol, 501 mg/dL; radioiodine uptake, 7% at 24 hr; protein-bound iodine (PBI), 2.8 mg/dL. B, After therapy for 18 mo, note the nasal development, increased luster and decreased pigmentation of hair, and maturation of the face. The height age was 5.5 yr; the bone age was 7 yr. There was a decided improvement in her general condition. Menarche occurred at 14 yr. The ultimate height was 155 cm (61 in). She graduated from high school. The disorder was well controlled with sodium-L-thyroxine daily.

Figure 559-4 A, Short stature (108 cm, <3rd percentile), generalized myxedema, sleepy expression, protuberant abdomen, and coarse hair are signs of hypothyroidism in this 12-yr-old boy. Body proportions are immature for his age (1.25 : 1). B, Same boy 4 mo after treatment. His height increased by 4 cm; note the marked change in body habitus owing to loss of generalized myxedema, improved muscle tone, and bright facial expression.

(From LaFranchi SH: Hypothyroidism, Pediatr Clin North Am 26:33–51, 1979.)

Some children have headaches and vision problems; they usually have hyperplastic enlargement of the pituitary gland, sometimes with suprasellar extension, after long-standing hypothyroidism; this condition, believed to be the result of thyrotroph hyperplasia, may be mistaken for a pituitary tumor (Chapter 551).Abnormal laboratory studies include hyponatremia, macrocytic anemia, hypercholesterolemia, and elevated CPK. Complications seen in severe hypothyroidism are noted in Table 559-4. All these changes return to normal with adequate replacement of T_4.

Table 559-4 PATHOGENESIS OF GENERAL COMPLICATIONS IN MANAGEMENT OF COMPLICATED HYPOTHYROIDISM

From Roberts CG, Landenson PW: Hypothyroidism, Lancet 363:793–803, 2004.

Diagnostic Studies

Children with suspected hypothyroidism should undergo measurement of serum free T₄ and TSH. Because the normal range for thyroid tests is slightly higher in children than adults, it is important to compare results to age-specific reference ranges. Measurement of antithyroglobulin and antiperoxidase (formerly, antimicrosomal) antibodies can pinpoint autoimmune thyroiditis as the cause. Generally, there is no indication for thyroid imaging. In cases with a goiter resulting from autoimmune thyroid disease, an ultrasound examination typically shows diffuse enlargement with scattered hypoechogenicity. Some children with acquired hypothyroidism and a goiter have a thyroid nodule discovered by palpation or neck sonography. Ultrasound examination is the most accurate method to follow nodule size and solid vs. cystic nature (Chapter 563.1). In children with a nodule and suppressed TSH, a radioactive iodine uptake and scan is indicated to determine if this is a “hot” or hyperfunctioning nodule. A bone age x-ray at diagnosis is useful, in that the degree of delay approximates duration and severity of hypothyroidism.

Treatment and Prognosis

Levothyroxine is the treatment of choice in children with hypothyroidism. The dose on a weight basis gradually decreases with age. For children 1-3 yr, the average L-T₄ dosage is 4-6 µg/kg/day; for 3-10 y4, 3-5 µg/kg/day; and for 10-16 yr, 2-4 µg/kg/day. Treatment should be monitored by measuring serum free T₄ and TSH every 4-6 mo as well as 6 wk after any change in dosage. In children with central hypothyroidism, where TSH levels are not helpful in monitoring treatment, the goal should be to maintain serum free T4 in the upper half of the normal reference range for age.

During the 1st yr of treatment, deterioration of schoolwork, poor sleeping habits, restlessness, short attention span, and behavioral problems might ensue, but these are transient; forewarning families about these manifestations enhances appropriate management. These may be partially ameliorated by starting at sub-replacement T₄ doses and advancing slowly. An occasional older child (8-13 yr) with acquired hypothyroidism may experience pseudotumor cerebri within the first 4 mo of treatment.

In older children, after catch-up growth is complete, the growth rate provides a good index of the adequacy of therapy. Periodic bone age x-rays are useful to monitor treatment and future growth potential. In children with long-standing hypothyroidism, catch-up growth may be incomplete (see Fig. 559-4). During the first 18 mo of treatment, skeletal maturation often exceeds expected linear growth, resulting in a loss of about 7 cm of predicted adult height; the cause is unknown.